Characterizing and Targeting ERBB2 Mutations in Invasive Lobular Carcinoma
侵袭性小叶癌中 ERBB2 突变的特征和靶向
基本信息
- 批准号:10749213
- 负责人:
- 金额:$ 5.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAntibody-drug conjugatesAutomobile DrivingBreastCadherinsCell LineCharacteristicsClinicalClinical ManagementClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCombined Modality TherapyComplementDataDependenceDiseaseDrug resistanceE-CadherinERBB2 geneEngineeringEnvironmentEpidermal Growth Factor ReceptorEstrogen receptor positiveEvolutionExhibitsFDA approvedFutureGenesGenetic TranscriptionGenomicsGoalsGrowthGrowth Factor ReceptorsHSP 90 inhibitionHeat-Shock Proteins 90HistologicIGF1R geneIn VitroInferiorInvestigationKnock-outLearningLobular CarcinomaMalignant Epithelial CellMediatingMessenger RNAMetastatic breast cancerMolecularMolecular ChaperonesMutationNatureNuclearNull LymphocytesOncogenicOrganoidsOutcomePatientsPhenotypePhysiciansPlasmaPre-Clinical ModelPrevalencePrognosisReceptor Protein-Tyrosine KinasesRecurrenceRegulationReportingRepressionResearch PersonnelResistanceRoleSamplingScientistSignal PathwaySignal TransductionSpecimenTestingThe Cancer Genome AtlasTherapeuticTrainingTyrosine Kinase InhibitorWomanXenograft procedurebreast cancer progressionclinically relevantclinically significanteffective therapyexperimental studygain of functiongenome editinghormone therapyin vitro Modelinfiltrating duct carcinomainnovationmRNA Expressionmalignant breast neoplasmmutantoverexpressionpatient subsetspermissivenessprotein expressionresponsetargeted treatmenttherapy resistanttranscriptome sequencingtranslational cancer researchtumortumor progression
项目摘要
PROJECT SUMMARY
Although invasive lobular carcinoma (ILC) accounts for 10-15% of breast cancer, there remains much to be
learned about the unique nature of this disease. Compared to invasive ductal carcinoma (IDC), ILC is
understudied, with distinct histological, genomic, and clinical characteristics. Despite key differences, women
with estrogen receptor-positive (ER+) ILC will most likely receive the same treatment as women with ER+ IDC
though often show inferior long-term outcomes.
Recently, the Lee-Oesterreich Lab and others have identified enrichment of ERBB2 mutations in ILC compared
to IDC. As ILC is characterized by loss of CDH1 (E-cadherin), our findings may suggest a potential interaction
between loss of CDH1 and mutations in ERBB2 in driving ILC tumor progression. As ERBB2 mutations usually
occur in the absence of ERBB2 amplification, there are currently no FDA-approved therapies targeting ERBB2
mutant ILC. Several clinical trials have reported promising efficacy of anti-HER2 tyrosine kinase inhibitors,
including neratinib, in patients with ERBB2 mutant ILC. However, resistance to these therapies is inevitable. In
order to identify the most effective combination therapies, the functional role of these recurrent ERBB2
mutations in ILC requires further investigation. Using a combination of clinical specimens, innovative in vitro
models and CRISPR-based genome editing, our proposal will determine the prevalence of ERBB2 mutations in
ctDNA collected from plasma samples of patients with metastatic breast cancer and investigate how these
mutations influence HER2 activation and downstream signaling pathways and sensitivity/resistance to
available anti-HER2 agents (Aim 1). We will also evaluate the effects of CDH1 knockout and re-expression on
HER2 signaling and degradation in order to understand the cooperation between loss of CDH1 and mutations
in ERBB2 in ILC and explore potential mechanisms of HER2 regulation by E-cadherin (Aim 2).
Results of this and future research will help inform clinicians and researchers of the mechanisms, clinical
relevance, and targetability of recurrent ERBB2 mutations and complement findings from ongoing clinical trials
to identify the most effective therapy combinations for patients with ERBB2 mutant ILC.
项目概要
尽管浸润性小叶癌 (ILC) 占乳腺癌的 10-15%,但仍有许多问题需要解决
了解了这种疾病的独特性质。与浸润性导管癌 (IDC) 相比,ILC 是
尚未得到充分研究,具有独特的组织学、基因组和临床特征。尽管存在重大差异,女性
雌激素受体阳性 (ER+) ILC 很可能会接受与 ER+ IDC 女性相同的治疗
尽管经常表现出较差的长期结果。
最近,Lee-Oesterreich 实验室和其他实验室发现,与 ILC 相比,ERBB2 突变富集
至 IDC。由于 ILC 的特点是 CDH1(E-钙粘蛋白)缺失,我们的研究结果可能表明潜在的相互作用
CDH1 缺失和 ERBB2 突变驱动 ILC 肿瘤进展之间的关系。由于 ERBB2 突变通常
发生在没有 ERBB2 扩增的情况下,目前尚无 FDA 批准的针对 ERBB2 的疗法
突变型 ILC。多项临床试验报告了抗 HER2 酪氨酸激酶抑制剂的良好疗效,
包括 neratinib,用于治疗 ERBB2 突变 ILC 患者。然而,对这些疗法的抵抗是不可避免的。在
为了确定最有效的联合疗法,这些复发性 ERBB2 的功能作用
ILC 突变需要进一步研究。采用临床标本组合,创新体外
模型和基于 CRISPR 的基因组编辑,我们的建议将确定 ERBB2 突变的流行率
从转移性乳腺癌患者的血浆样本中收集 ctDNA,并研究这些样本如何
突变影响 HER2 激活和下游信号通路以及敏感性/耐药性
可用的抗 HER2 药物(目标 1)。我们还将评估 CDH1 敲除和重新表达对
HER2 信号传导和降解,以了解 CDH1 丢失和突变之间的协同作用
ILC 中的 ERBB2 并探索 E-钙粘蛋白调节 HER2 的潜在机制(目标 2)。
这项研究和未来的研究结果将有助于临床医生和研究人员了解其机制、临床
正在进行的临床试验中复发性 ERBB2 突变和补体发现的相关性和靶向性
确定针对 ERBB2 突变 ILC 患者最有效的治疗组合。
项目成果
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